Project Summary/Abstract Lynch syndrome (LS) is the most common form of inherited colorectal cancer risk. People with Lynch syndrome are also at increased risk for endometrial, ovarian, gastric, small bowel, and renal cancers. Importantly, well-established clinical guidelines with strong evidence exist for cancer treatment, screening, and prevention in individuals with LS. Identification of individuals with LS is accomplished through a variety of techniques, including family and medical history evaluation, computational models, or tumor testing. The systematic screening of all colorectal tumors for LS was first recommended by the Evaluation of Genetic Application in Practice and Prevention (EGAPP) working group in 2009 and has been designated high priority by the National Academies of Science, Engineering, and Medicine working group and by the Blue Ribbon Panel. The potential public health impact to reduce cancer morbidity and mortality of this intervention supports this priority, as effective implementation of LS screening will help meet the goals of the Cancer Moonshot as well as demonstrate the promise of precision medicine. Currently, implementation of LS screening in healthcare systems remains suboptimal for a variety of reasons. LS screening involves the coordination of multiple departments and individuals across an organization, which is often difficult in large, complex, healthcare systems. Therefore, the overarching goal of this project is to utilize tools from implementation science to describe, explain, and compare decision making and other variations in LS screening implementation across multiple healthcare systems to create and evaluate in a real world setting an organizational toolkit to facilitate implementation of LS screening. Our specific aims are to (1) Describe variation in LS screening implementation across multiple healthcare systems; then (2) Explain practice variation and determine factors associated with optimal implementation; and (3) Determine the relative effectiveness, efficiency, and costs of different LS screening protocols by healthcare system; and finally to (4) Develop and test in a natural environment an organizational toolkit for LS screening. This toolkit will enable effective implementation of LS screening programs; ultimately preventing needless suffering of patients and their family members from preventable cancers, decreasing waste in healthcare system costs, and informing strategies to facilitate the promise of precision medicine.